tbuckley/cabot-search huggingface dataset:
RADT-36. A SINGLE-CENTRE EXPERIENCE WITH HYPERARC FRACTIONATED STEREOTACTIC RADIOSURGERY [FSRS] FOR BENIGN BRAIN TUMOURS
Authors: Holly Hicks, Mohd Samuji, Laura Barry, Erica Bennett, Eoin Toomey, Paul Kelly
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Treating benign brain tumours with fSRS may have radiobiologic and clinical advantages, such as lower rates of symptomatic oedema and radionecrosis[1]. HyperArc (HA, Varian Medical System) is an isocentric VMAT technique developed for non-coplanar, MLC-based stereotactic radiotherapy with automated optimizations and delivery. Here we report our initial clinical experience of HyperArc fSRS in treating benign brain tumours. MATERIALS AND METHODS We retrospectively reviewed 21 cases of benign brain tumours treated at the Bon Secours Radiotherapy Cork between May 2020-May 2023. Clinical and dosimetric parameters are reported. RESULTS A total of 21 patients were treated in a total of 105 SRS fractions, all using a 5-fraction regimen (5x5Gy, N = 20). The commonest tumour was meningioma (N = 9), followed by vestibular schwannoma (N = 7) and pituitary adenoma (N = 5). Median patient age was 59 years (range 26-86). Median PTV was 4.65 cc (IQR 1.9-14.6), median number of arcs was 4 (range 3-4), median PTV coverage was 99.6 % (IQR 98.0-99.9). Median prescription isodose was 79%. Median Paddick conformity index and gradient index was 0.86 (IQR 0.83-0.98) and 3.0 (IQR 2.9-3.2) respectively. Median follow-up was 7 months. No patient suffered from toxicity ≥ grade 2 (Common Toxicity Criteria, Version 5). Only 2/21 patients required steroid therapy during fSRS. No patient had a seizure. CONCLUSION HyperArc fSRS is a feasible option for benign brain tumours. Initial clinical experience in terms of plan quality and acute toxicity is encouraging. fSRS for benign brain tumours should be prospectively studied. REFERENCES: 1. Lehrer EJ et al IJROBP 2019 Mar1;103(3):610-630
SURG-17. COMPARABLE SAFETY PROFILE BETWEEN NEURO-ONCOLOGY PROCEDURES INVOLVING STEREOTACTIC NEEDLE BIOPSY (SNB) FOLLOWED BY LASER INTERSTITIAL THERMAL THERAPY (LITT) AND LITT ALONE PROCEDURES
Authors: Mayur Sharma, Truong Do, Elise Palzer, Jared Huling, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Tissue diagnosis through stereotactic needle biopsy (SNB) is often needed prior to laser interstitial thermal therapy (LITT). Whether these procedures should be performed in the same surgery or in separate surgeries remain unclear. As a first step to address this question, we assess safety profile of procedures involving LITT alone versus SNB+LITT. METHODS Using International Classification of Disease (ICD) codes, we queried the National Readmissions Database (NRD, 2010-2018) for malignant brain tumor patients who underwent either 1) LITT alone or 2) elective LITT in combination with SNB (SNB+LITT). Survey regression methods were utilized. Additionally, the procedural outcome of LITT or SNB+LITT performed by the senior surgeon (2014-2022) were reviewed. RESULTS During the study period, an estimated 678 malignant brain tumor patients underwent LITT alone versus 373 patients that underwent SNB+LITT. Patients undergoing LITT and SNB+LITT exhibited statistically comparable median lengths of hospital stay (IQR; LITT = 2 day [1, 3]; SNB+LITT = 1 day [1, 3]; p = 0.405) and likelihood of routine discharge (LITT = 73.5%; SNB+LITT = 81.1%; p = 0.068). the odds of 30-day medical or neurological readmissions were comparable between LITT and SNB+LITT treated patients (all p ≥ 0.793) In the single surgeon experience of 218 procedures performed over an eight year period (2014-2022), the complications (LITT = 3.9%; SNB+LITT = 2.6%, p = 0.709), discharge within 48 hours (LITT = 84.5%; SNB+LITT = 87.8%; p = 0.556), routine discharge (LITT = 91.3%; SNB+LITT = 93.9%; p = 0.604), and unplanned 30-day readmission (LITT = 3.9%; SNB+LITT = 1.7%; p = 0.423) were similarly comparable between LITT and SNB+LITT. The most common complications were: hemorrhage (n = 3) and LITT-associated edema (n = 3) followed by hydrocephalus (n = 1). Of the 115 patients who underwent SNB+LITT, the frozen pathology diagnosis was revised on final pathology in two patients (2/115 or 1.7%). CONCLUSION The length of hospital stay, the likelihood of routine discharge, and 30-day readmission for malignant brain tumor patients who underwent LITT and SNB+LITT were comparable.
EPCO-23. EFFECTS OF H3.3G34V MUTATION ON GENOMIC H3K36 AND H3K27 METHYLATION PATTERNS IN ISOGENIC PEDIATRIC GLIOMA CELLS
Authors: Tina Huang, Andrea Piunti, Jin Qi, Elizabeth Bartom, Amanda Saratsis
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas (pHGGs). This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase). Consequently, reduced H3K36me3 is observed on H3.3G34V nucleosomes relative to wild-type, contributing to genomic instability and driving a distinct gene expression signature associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3.3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3.3G34V mutant protein in pediatric glioma on H3K36me3, H3K27me3 and H3.3 enrichment in vitro. METHODS Experiments were conducted using an established H3.3G34V mutant patient-derived pediatric high-grade glioma cell line (KNS42), and Histone H3.3 wild-type human astrocytes (NHAs). Lentiviral delivery of a doxycycline-inducible RNAi vector targeted against H3F3A was transduced to KNS42 cells to knock down H3.3G34V protein expression. Cell lines were then compared via ChIP-Seq, Western Blot, proliferation and viability studies. RESULTS We found that the doxycycline-inducible shRNA knockdown of mutant H3F3A encoding the H3.3G34V protein resulted in loss of H3.3G34V enrichment and increased H3K36me3 enrichment throughout the genome. After knockdown, H3.3G34V enrichment was preserved at loci observed to have the greatest H3.3G34V and H3K36me3 enrichment prior to knockdown. Induced expression of mutant H3.3G34V protein in vitro was insufficient to induce genomic H3K36me3 enrichment patterns observed in H3.3G34V mutant glioma cells. We also observed strong co-enrichment of H3.3G34V and wild-type H3.3 protein, as well as greater H3K27me3 enrichment, in cells expressing H3.3G34V. CONCLUSION Our study demonstrates the effects of H3.3G34V mutant protein on genomic H3K36me3, H3K27me3 and H3.3 enrichment patterns in isogenic cell lines.
NCOG-28. RECURRENCE OF PLEOMORPHIC XANTHOASTROCYTOMA PRESENTING WITH DIFFUSE LEPTOMENINGEAL SPREAD
Authors: Jessica White, Giovanna Grigsby-Rocca, Camilo Bermudez, Bryan Neth, Joon Uhm, Rafid Mustafa
Journal: Neuro-Oncology (2023)

Abstract Pleomorphic xanthoastrocytomas (PXAs) are rare primary brain tumors that mainly affect children and young adults. We report a case of recurrent PXA in an adult and review the literature. To our knowledge, this is the first adult report highlighting clinical, CSF, and imaging findings of recurrent PXA with leptomeningeal spread. A 60-year-old woman presented with a 2-month history of fluctuating mental status, aphasia, low-back pain, progressive paraparesis, and urinary retention. She was previously diagnosed with a left temporal PXA 17 years prior and underwent gross total resection with no evidence of tumor recurrence for the next several years. Approximately 10 months prior to her current presentation, she was found to have radiographic recurrence of the left temporal PXA. She underwent gross total resection, with final pathology revealing anaplastic transformation, WHO grade 3, BRAF V600E mutation positive. She next underwent photon radiotherapy, and chemotherapy with temozolomide. She had good clinical and radiographic response to treatment for 8 months prior to developing her current symptomatology. MRI of the brain and spine showed local recurrence with new diffuse contrast enhancement of the spinal cord and nerve roots. Cerebrospinal fluid (CSF) analysis showed a total nucleated cell count of 10/mcL, protein &amp;gt;1250 mg/dL, glucose &amp;lt; 20 mg/dL, and xanthochromia. CSF cytology was positive for malignant cells consistent with PXA. Although PXA is often associated with a favorable prognosis, recurrence with anaplastic transformation can be associated with dissemination throughout the nervous system and worse outcomes. Despite the rarity of such cases, clinicians should remain vigilant, especially when anaplastic transformation occurs. Early detection of leptomeningeal involvement through thorough CSF analysis and appropriate imaging can facilitate prompt intervention and potentially improve patient outcomes.
BIOM-17. WHOLE GAIN OF CHROMOSOME 19, NOT CO-GAIN OF CHROMOSOMES 19 AND 20, IS A FAVORABLE PROGNOSTIC BIOMARKER IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Nicholas Nuechterlein, Patrick Cimino, Eric Holland
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND IDH-wildtype glioblastoma carries an abysmal prognosis, but long-term survivors exist. Previous studies have suggested that co-gain of chromosomes 19 and 20 (+19/+20) is a favorable prognostic marker. We sought to validate this claim and investigate whether gain of chromosome 19 (+19) is a superior prognostic indicator. METHODS We collected somatic copy number alteration data for primary glioblastoma tumors from TCGA (N = 356) and paired primary (N = 169) and recurrent (N = 167) glioblastoma tumors from GLASS. We assessed the frequency of these events and conducted survival analyses with univariate and multivariate Cox proportional hazard models to examine the association between +19/+20 and +19 and patient outcomes. RESULTS Among primary glioblastomas, the frequency of +19/+20 (20.8% vs. 23.7%) and +19 (34.6% vs. 36.7%) did not differ between TCGA and GLASS. However, the presence of +19/+20 was significantly reduced in GLASS recurrent tumors compared to primary tumors (14.3%, p = 0.04), while +19 without +19/+20 was unchanged (13.8%), indicating that +19/+20 is selected against in recurrent glioblastoma. Tumors harboring +19/+20 did not exhibit improved overall survival (OS) or progression-free survival (PFS) in TCGA (p = 0.21 and p = 0.14, respectively), nor did they demonstrate improved OS in GLASS (p = 0.32). Conversely, tumors with +19 showed significantly better OS and PFS in TCGA (HR = 1.4, p&amp;lt; 0.01; HR = 1.5, p&amp;lt; 0.01, respectively) and improved OS in GLASS (HR = 1.6, p&amp;lt; 0.01). In multivariate survival analyses, +19 remained a prognostic factor independent of +19/+20, patient sex, age, MGMT promoter methylation status, and KPS in TCGA (p&amp;lt; 0.05) and +19/+20 and age in GLASS (p = 0.01). CONCLUSION Although previous studies have suggested that +19/+20 is a positive prognostic biomarker in glioblastoma, our findings indicate that this assertion should be reevaluated. Our results demonstrate that +19 is associated with favorable outcomes in the TCGA and GLASS datasets, whereas +19/+20, while possibly selected against in recurrent glioblastomas, is not.
TMIC-79. LIPOCALIN-2 MEDIATES CELL-INTRINSIC FUNCTIONS IN GLIOBLASTOMA
Authors: Sabrina Wang, Daniel Silver, Loic Deleyrolle, Justin Lathia
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common primary brain tumor with a median survival of 17-20 months. Despite therapeutic treatments including surgery, radiation, chemotherapy, a population of GBM cells, termed cancer stem cells (CSCs) are radio-resistant and chemo-resistant, leading to mortality of the patient. CSCs also have altered metabolic profiles and have an enhanced capacity to scavenge nutrients from their microenvironment, including iron. Lipocalin-2 (LCN2) functions to sequester iron and is traditionally considered an inflammatory marker through its function of limiting iron for bacterial usage; it has also been described to have both a pro and anti-tumorigenic and has context-dependent functions depending on iron status. LCN2 has been shown to be important in brain metastasis, but its role in GBM is still largely unknown. To assess a cell-intrinsic function for LNC2, we added recombinant LCN2 to low LCN2-secreting mouse GBM cell models and observed that proliferation also increased. When we knocked down LCN2 in our higher LCN2 secreting cell lines, we observed that knockdown cells had decreased viability and growth, which was not mediated by apoptosis, but rather, ferroptosis. When these cells were subsequently engrafted into wild-type mice, we observed an increase in survival. This effect was also phenocopied when the cells were implanted into LCN2 knockout mice, suggesting the tumor-intrinsic effect overpowered the global knockout model. Lastly, to investigate how LCN2 plays a role in the GBM microenvironment, we orthotopically implanted syngeneic mouse GBM cells into male and female LCN2 knockout and wild-type mice. We observed no survival difference, further suggesting that LCN2 does not function in an extrinsic manner. Taken together, these data suggest that LCN2 affects proliferation and tumorigenesis, and is another avenue to understanding the complexity of GBM biology. Strategies to reduce LCN2 in GBM may provide a therapeutic target for GBM in the future.
EXTH-74. TUMOR PHARMACOKINETICS AND PHARMACODYNAMICS IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA TREATED WITH THE PRMT5 INHIBITOR SKL27969
Authors: An-Chi Tien, Tigran Margaryan, Jennifer Molloy, James McNamara, William Knight, Raymond Hon, Zorana Opachich, Ernesto Luna Melendez, Mackenna Elliott, Connor White, Nader Sanai, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2023)

Abstract Epigenetic regulation plays a key role in the development of several cancers, including glioblastoma (GBM). Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising therapeutic target for GBM. PRMT5 is the primary type II methyltransferase that catalyzes symmetric arginine dimethylation in multiple proteins. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and radiation sensitization properties of SKL27969, a highly selective PRMT5 inhibitor, in orthotopic patient-derived xenograft (PDX) models of GBM. Mice with intracranial tumors were randomized to 50 mg/kg (oral) SKL27969 vs. placebo for two cycles either alone or in combination with radiation. SKL27969 levels in plasma and contrast-enhancing tumor tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unbound fractions were determined by equilibrium dialysis. Immunohistochemistry was performed to assess levels of SDMA, phospho-Histone H3, pH2AX, and cleaved caspase 3 (CC3). For survival studies, mice with intracranial tumors were randomized into four cohorts – vehicle, radiotherapy, SKL27969 monotherapy, and SKL27969 plus radiotherapy. The median brain-to-plasma and tumor-to-plasma partition coefficients of unbound SKL27969 were 1.8 and 2.9, respectively – indicating favorable brain and tumor penetration ability of SKL27969. A decrease in SDMA (+) cells (54% vs. 0.1%, p &amp;lt; 0.001) indicated PRMT5 inhibition and was accompanied by an increase in CC3 (+) cells (0.7% vs. 1.2%, p = 0.01). SKL27969 is well tolerated, achieves pharmacologically relevant unbound concentrations in GBM PDX models, and is associated with significant target modulation. Ongoing studies are evaluating in vivo survival benefit from combining PRMT5 inhibition with radiation therapy.
CSIG-11. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA
Authors: Truman Knowles, Shejuan An, Tina Huang, Jin Qi, Amanda Saratsis
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n = 6) and controls (normal human astrocytes n = 1, human neural stem cells n = 1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC&amp;gt;2 or &amp;lt;-2, p&amp;lt; 0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
NCOG-27. LONG-TERM OUTCOMES OF GAMMA KNIFE RADIOSURGERY FOR GROWING MENINGIOMA
Authors: Yeong Jin Kim
Journal: Neuro-Oncology (2023)

Abstract Gamma knife radiosurgery (GKRS) has become an effective treatment modality for intracranial meningioma. However, the role of GKRS in managing growing meinigoma during follow-up remains uncertain. This study aims to investigate the long-term outcome after GKRS treatment on meningioma for growing meningioma at follow-up. A retrospective analysis was conducted on patients who underwent GKRS as primary treatment for growing meingiomas between 2004 and 2021. Growing meningioma was defined as a &amp;gt;10% increase in volume compared to the previous imaging. Fifty-nine patients who received GKRS as initial treatment were included in this study with minimum follow-up period of 12 months. Patient clinical-radiological data, tumor characteristics and procedural details were analyzed. Tumor progression and regression were defined as a &amp;gt;10% increase or decrease in volume, respectively, compared to pre-GKRS image. Tumor volumes within ±10% of pre-GKRS volume were considered stable. At a median follow-up of 41 months (range 15-197 months), tumor volume was unchanged in 16 patients (27.1%), decreased in 41 patients (69.5%), and increased in 2 patients (3.4%). In multivariate analysis, growth rate was significantly associated with tumor progression (hazard ratio [HR]=2.059, 95% confidence interval [CI]=1.028-4.123, p=0.042). Eleven patients (18.6%) experienced new or worsening symptoms. In multivariate analysis, factors predicting new or worsening neurological function were preexisting symptoms (HR=7.159, 95% CI=1.468-34.911, p=0.015) and tumor calcification (HR=11.921, 95% CI=2.400-59.202), p=0.002), and pre-existing peritumoral edema (HR=9.751, 95% CI=1.666-57.058, p=0.012). GKRS demonstrates a high tumor control rate as well as an acceptable complication rate in growing meningioma. Effective tumor control is more likely in patients with slow-growing tumor.
EXTH-14. MRNA-LOADED EXOSOMES FOR TARGETED GLIOBLASTOMA IMMUNOTHERAPY
Authors: Shiyan Dong, Abin Antony, Yifan Wang, Betty Kim, Wen Jiang
Journal: Neuro-Oncology (2023)

Abstract Recent successes of mRNA therapeutics against pathogenic infections have increased interest in their investigations for other human diseases including cancer. However, precisely delivering the genetic cargo to cells and tissues of interest remains challenging. Extracellular vesicles such as exosomes have gained increased interest recently as potential nucleic acid and drug carriers given their favorable immunogenic profile, long circulatory half-life, and ability to cross biological barriers such as blood-brain barrier. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded exosomes. This was achieved using a microfluidic electroporation approach where a combination of nano- and milli-second pulse electroporations produced a large quantity of IFN-γ mRNA-loaded exosomes with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic exosomes (imExo) selectively targeted glioblastoma cells and generated potent antitumor activities in vivo, including against tumors intrinsically resistant to immunotherapy. Together, these results provide a new adaptive approach to engineering mRNA-loaded exosomes with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.
NIMG-84. COMPARISON OF TRADITIONAL AND ADVANCED DEEP-LEARNING PATIENT SPECIFIC REGISTRATION METHODS IN PRESERVING TUMOR HABITAT IN GLIOBLASTOMA TUMORS: A PRELIMINARY STUDY
Authors: Apoorva Safai, Gustavo Pineda, Ipsa Yadav, Marwa Ismail, Pallavi Tiwari
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Registration of patient specific pre and post operative MRI scans in Glioblastoma patients is crucial to assess tumor progression, effect of radiation, and chemotherapy and survival prediction. However, in brain tumors longitudinal registration is challenging as tumor resection and mass effects causes tissue deformations and missing intensity correspondence across longitudinal scans. In this study, we compared effectiveness of traditional registration algorithms with state-of-the-art computationally extensive deep learning (DL) models in preserving intensity of tumor regions. METHODS Brain MRI scans (T1w,T1c,T2w,FLAIR) of 14 glioblastoma patients with first (tp1), intermediate (tp2) and follow up post operative scans (tp3) were obtained from two publicly available dataset (LUMIERE, XCURE). Preprocessing involved co-registration of all modalities within a timepoint, skull stripping, and uniformity in image dimensions, orientation, and origin across all timepoints. Tumor scans at tp2 and tp3 were registered to tp1 for all modalities independently, using different registration algorithms such as the traditional affine and symmetric diffeomorphic (SyN) registration with and without tumor masks using the ANTs software, along with the MICCAI-registration challenge winner DL algorithm (DIRAC). Intensity distribution of registered and unregistered scans for tp2 and tp3 were compared using the earth mover’s distance (EMD). RESULTS Traditional affine (tp2-0.074±0.06, tp3:0.058±0.051) and SyN (tp2-0.048±0.031 ,tp3:0.075±0.074) registration algorithm using T2w modality provided lower average EMD than DL method (tp2-0.624±0.69,tp3-0.595±0.67). Intensity distribution was better preserved for scans from intermediate timepoints compared to the post operative scans. CONCLUSION Our preliminary assessment suggests that traditional registration methods when implemented on pre-aligned MRI scans may better preserve image intensities in brain tumors scans compared to advanced and computationally expensive DL methods.